Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P21817 (RyR1)
1,154 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ryanodine receptors (RyRs) are a family of intracellular Ca(2+) channels that are regulated by calmodulin (CaM). At low Ca(2+) concentrations (<1 microM), CaM activates RyR1 and RyR3 and inhibits RyR2. At elevated Ca(2+) concentrations (>1 microM), CaM inhibits all three RyR isoforms. Here we report that the regulation of recombinant RyR3 by CaM is sensitive to redox regulation. RyR3 in the presence of reduced glutathione binds CaM with 10-15-fold higher affinity, at low and high Ca(2+) concentrations, compared to in the presence of oxidized glutathione. However, compared to RyR1 assayed at low Ca(2+) concentrations under both reducing and oxidizing conditions, CaM binds RyR3 with reduced affinity but activates RyR3 to a greater extent. Under reducing conditions, RyR1 and RyR3 activities are inhibited with a similar affinity at [Ca(2+)] > 1 microM. Mutagenesis studies demonstrate that RyR3 contains a single conserved CaM binding site. Corresponding amino acid substitutions in the CaM binding site differentially affect CaM binding and CaM regulation of RyR3 and those of the two other isoforms. The results support the suggestion that other isoform dependent regions have a major role in the regulation of RyRs by CaM [Yamaguchi et al. (2004) J. Biol. Chem. 279, 36433-36439].
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PMID:Calmodulin regulation and identification of calmodulin binding region of type-3 ryanodine receptor calcium release channel. 1627 54

This study examined the localization and functional expression of ryanodine receptors (RyR) within the cochlea using a combination of reverse transcription-polymerase chain reaction, immunolabeling techniques, and confocal Ca2+ imaging. All three RyR isoform mRNA transcripts were detected in the adult rat cochlea. Immunoperoxidase and immunofluorescence labeling showed that the three isoforms were differentially expressed. The most pronounced RyR protein expression, involving all three isoforms, occurred in the cell bodies of the spiral ganglion neurons. RyR3 labeling extended to the synaptic terminals innervating the inner and outer hair cells. RyR2 expression also occurred in the inner hair cells and supporting cells of the organ of Corti, while cells associated with ion homeostasis in the cochlea, such as the interdental cells of the spiral limbus (RyR1), and the epithelial cells of the spiral prominence and basal cells of the stria vascularis (RyR2 and RyR3), were also immunopositive. The functionality of RyR-gated Ca2+ stores in the spiral ganglion neurons was shown by confocal calcium imaging of fluo-4 fluorescence in rat cochlear slices. Caffeine (5 mM) evoked an increase in intracellular Ca2+ concentration in the cell bodies of the spiral ganglion neurons which occurred inthe absence of external Ca2+. Ryanodine (50 nm-1 microM) evoked comparable increases in intracellular Ca2+ concentration. These findings suggest that RyR-mediated Ca2+ release may be involved in auditory neurotransmission, sound transduction, and cochlear electrochemical homeostasis.
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PMID:Differential expression of ryanodine receptors in the rat cochlea. 1628 50

The ryanodine receptor (RyR) is a widely expressed intracellular calcium (Ca(2+))-release channel regulating processes such as muscle contraction and neurotransmission. Snapin, a ubiquitously expressed SNARE-associated protein, has been implicated in neurotransmission. Here, we report the identification of snapin as a novel RyR2-interacting protein. Snapin binds to a 170-residue predicted ryanodine receptor cytosolic loop (RyR2 residues 4596-4765), containing a hydrophobic segment required for snapin interaction. Ryanodine receptor binding of snapin is not isoform specific and is conserved in homologous RyR1 and RyR3 fragments. Consistent with peptide fragment studies, snapin interacts with the native ryanodine receptor from skeletal muscle, heart and brain. The snapin-RyR1 association appears to sensitise the channel to Ca(2+) activation in [(3)H]ryanodine-binding studies. Deletion analysis indicates that the ryanodine receptor interacts with the snapin C-terminus, the same region as the SNAP25-binding site. Competition experiments with native ryanodine receptor and SNAP25 suggest that these two proteins share an overlapping binding site on snapin. Thus, regulation of the association between ryanodine receptor and snapin might constitute part of the elusive molecular mechanism by which ryanodine-sensitive Ca(2+) stores modulate neurosecretion.
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PMID:Ryanodine receptor interaction with the SNARE-associated protein snapin. 1672 44

Calcium (Ca(2+)) signaling plays a pivotal role in the function of dendritic cells (DC). The Type 1 ryanodine receptor (RyR), a major intracellular Ca(2+) channel, is highly expressed in immature DC. We therefore investigated whether RyR1 plays a role in DC development and function by studying properties of DC derived from wild-type (WT) and RyR1 null [knockout (KO)] mice. Fetal liver cells from WT and RyR1 KO mice retained full hematopoietic competence. Adoptive transfer of these cells into congenic hosts resulted in the generation of functionally equivalent DC populations. WT and RyR1 KO DC exhibited a similar capacity to mature in response to inflammatory and/or activation stimuli, to endocytose antigen, and to stimulate T cell proliferation. Moreover, the absence of RyR1 did not lead to de novo expression of RyR2 or RyR3. WT and RyR KO DC express all three isoforms of inositol 1,4,5-trisphosphate receptor (IP(3)R), although Type 3 IP(3)R gene transcripts are predominant. Further, IP(3)-mediated Ca(2+) transients proceed normally after inhibition of RyRs with dantrolene. Signaling via IP(3)R may therefore be sufficient to drive essential DC Ca(2+) signaling processes in the absence of RyR expression or function.
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PMID:IP3Rs are sufficient for dendritic cell Ca2+ signaling in the absence of RyR1. 2935 Aug 72

Two isoforms of ryanodine receptors are expressed in skeletal muscles, RyR1 and RyR3. We investigated the relative level of expression of RyRs in developing murine skeletal muscles using [3H]ryanodine binding and immunoprecipitation experiments. In the diaphragm RyR3 accounted for 11% of total RyRs in 5-day-old mice and for 3% of total RyRs in 60-day-old mice. In hindlimb muscles, RyR3 accounted for 3% and 1% of total RyRs in 5-day-old and adult mice, respectively. The activity of RyR1 channels in native microsomal vesicles from murine muscles was found to be as low as 35% of that measured after CHAPS exposure, while no inhibition was observed for RyR3. CHAPS sensitivity of recombinant RyR1 and RyR3 expressed in HEK293 cells was also investigated. The activity of recombinant RyR1 but not RyR3 channels was found to be inhibited in native conditions, suggesting that this property may not be dependent on a muscle environment.
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PMID:Expression and functional activity of ryanodine receptors (RyRs) during skeletal muscle development. 1711 45

We have defined regions of the skeletal muscle ryanodine receptor (RyR1) essential for bidirectional signaling with dihydropyridine receptors (DHPRs) and for the organization of DHPR into tetrad arrays by expressing RyR1-RyR3 chimerae in dyspedic myotubes. RyR1-RyR3 constructs bearing RyR1 residues 1-1681 restored wild-type DHPR tetrad arrays and, in part, skeletal-type excitation-contraction (EC) coupling (orthograde signaling) but failed to enhance DHPR Ca(2+) currents (retrograde signaling) to WT RyR1 levels. Within this region, the D2 domain (amino acids 1272-1455), although ineffective on its own, dramatically enhanced the formation of tetrads and EC coupling rescue by constructs that otherwise are only partially effective. These findings suggest that the orthograde signal and DHPR tetrad formation require the contributions of numerous RyR regions. Surprisingly, we found that RyR3, although incapable of supporting EC coupling or tetrad formation, restored a significant level of Ca(2+) current, revealing a functional interaction with the skeletal muscle DHPR. Thus, our data support the hypotheses that (i) the structural/functional link between RyR1 and the skeletal muscle DHPR requires multiple interacting regions, (ii) the D2 domain of RyR1 plays a key role in stabilizing this interaction, and (iii) a form of retrograde signaling from RyR3 to the DHPR occurs in the absence of direct protein-protein interactions.
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PMID:Bidirectional signaling between calcium channels of skeletal muscle requires multiple direct and indirect interactions. 1717 44

Stimuli are translated to intracellular calcium signals via opening of inositol trisphosphate receptor and ryanodine receptor (RyR) channels of the sarcoplasmic reticulum or endoplasmic reticulum. In cardiac and skeletal muscle of amphibians the stimulus is depolarization of the transverse tubular membrane, transduced by voltage sensors at tubular-sarcoplasmic reticulum junctions, and the unit signal is the Ca(2+) spark, caused by concerted opening of multiple RyR channels. Mammalian muscles instead lose postnatally the ability to produce sparks, and they also lose RyR3, an isoform abundant in spark-producing skeletal muscles. What does it take for cells to respond to membrane depolarization with Ca(2+) sparks? To answer this question we made skeletal muscles of adult mice expressing exogenous RyR3, demonstrated as immunoreactivity at triad junctions. These muscles showed abundant sparks upon depolarization. Sparks produced thusly were found to amplify the response to depolarization in a manner characteristic of Ca(2+)-induced Ca(2+) release processes. The amplification was particularly effective in responses to brief depolarizations, as in action potentials. We also induced expression of exogenous RyR1 or yellow fluorescent protein-tagged RyR1 in muscles of adult mice. In these, tag fluorescence was present at triad junctions. RyR1-transfected muscle lacked voltage-operated sparks. Therefore, the voltage-operated sparks phenotype is specific to the RyR3 isoform. Because RyR3 does not contact voltage sensors, their opening was probably activated by Ca(2+), secondarily to Ca(2+) release through junctional RyR1. Physiologically voltage-controlled Ca(2+) sparks thus require a voltage sensor, a master junctional RyR1 channel that provides trigger Ca(2+), and a slave parajunctional RyR3 cohort.
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PMID:Ca(2+) sparks operated by membrane depolarization require isoform 3 ryanodine receptor channels in skeletal muscle. 1736 Mar 29

Ca2+ sparks are localized intracellular Ca2+ release events from the sarcoplasmic reticulum in muscle cells that result from synchronized opening of ryanodine receptors (RyR). In mammalian skeletal muscle, RyR1 is the predominant isoform present in adult skeletal fibers, while some RyR3 is expressed during development. Functional studies have revealed a differential role for RyR1 and RyR3 in the overall Ca2+ signaling in skeletal muscle, but the contribution of these two isoforms to Ca2+ sparks in adult mammalian skeletal muscle has not been fully examined. When enzyme-disassociated, individual adult skeletal muscle fibers are exposed to an osmotic shock, the resting fiber converts from a quiescent to a highly active Ca2+ release state where Ca2+ sparks appear proximal to the sarcolemmal membrane. These osmotic shock-induced Ca2+ sparks occur in ryr3(-/-) muscle with a spatial distribution similar to that seen in wild type muscle. Kinetic analysis reveals that systemic ablation of RyR3 results in significant changes to the initiation, duration and amplitude of individual Ca2+ sparks in muscle fibers. These changes may reflect the adaptation of the muscle Ca2+ signaling or contractile machinery due to the loss of RyR3 expression in distal tissues, as biochemical assays identify significant changes in expression of myosin heavy chain protein in ryr3(-/-) muscle.
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PMID:Systemic ablation of RyR3 alters Ca2+ spark signaling in adult skeletal muscle. 1741 17

Ryanodine receptors (RyRs) are intracellular Ca(2+) channels that mediate the release of calcium from internal stores and therefore play an important role in Ca(2+) signaling and homeostasis. Three RyR isoforms have been described thus far, and various areas of brain are known to express each of them. It is well established that neurons can express different RyR isoforms, but it is not known whether microglial cells do so. In the present study we showed that cultured human microglia from both fetal and adult brain specimens express mRNA for RyR1 and RyR2, whereas RyR3 mRNA can be detected only in fetal microglial cells. Calcium spectrofluorometry showed that high levels of the RyR agonist 4-chloro-m-cresol (4-CmC, 1-5 mM) induced elevation of intracellular Ca(2+) concentration ([Ca(2+)](i)) in both types of cultured human microglial cells. This effect was attenuated by the RyR antagonist 1,1'-diheptyl-4,4'-bipyridinium dibromide (DHBP, 10 microM). Neurotoxicity of conditioned medium from human microglia and THP-1 monocytic cells stimulated with a combination of interferon-gamma (IFN-gamma) with either lipopolysaccharide (LPS) or alpha-synuclein was diminished by DHBP. It was also diminished by 4-CmC at concentrations approximately 100-fold lower than those used to stimulate intracellular Ca(2+) release. These data indicate that human microglial cells express functional RyRs and that selective RyR ligands exert antineurotoxic action on this cell type. Therefore, RyR ligands may represent a novel class of compounds that have utility in reducing microglial-mediated inflammation, which is believed to contribute to the pathogenesis of a number of neurodegenerative disorders including Alzheimer's disease and Parkinson's disease.
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PMID:Functional ryanodine receptors are expressed by human microglia and THP-1 cells: Their possible involvement in modulation of neurotoxicity. 1752 17

Activation of inositol-1,4,5-trisphosphate receptors (InsP(3)Rs) and ryanodine receptors (RyRs) can lead to the release of Ca(2+) from intracellular stores and propagating Ca(2+) waves. Previous studies of these proteins in neurons have focused on their distribution in adult tissue, whereas, recent functional studies have examined neural tissue extracted from prenatal and young postnatal animals. In this study we examined the distribution of InsP(3)R isotypes 1-3 and RyR isotypes 1-3 in rat hippocampus during postnatal maturation, with a focus on InsP(3)R1 because it is most prominent in the hippocampus. InsP(3)R1 was observed in pyramidal cells and granule cells, InsP(3)R2 immunoreactivity was observed in perivascular astrocytes and endothelial cells, and InsP(3)R3 immunoreactivity was detected in axon terminals located in stratum pyramidale of CA1 and microvessels in stratum radiatum. RyR1 immunolabeling was enriched in CA1, RyR2 was most intense in CA3 and the dentate gyrus, and RyR3 immunolabeling was detected in all subfields of the hippocampus, but was most intense in stratum lacunosum-moleculare. During maturation from 2 to 10 weeks of age there was a shift in InsP(3)R1 immunoreactivity from a high density in the proximal apical dendrites to a uniform distribution along the dendrites. Independent of age, InsP(3)R1 immunoreactivity was observed to form clusters within the primary apical dendrite and at dendritic bifurcations of pyramidal neurons. As CA1 pyramidal neurons matured, InsP(3)R1 was often co-localized with the Ca(2+) binding protein calbindin D-28k. In contrast, InsP(3)R1 immunolabel was never co-localized with calbindin D-28k immunopositive interneurons located outside of stratum pyramidale or with parvalbumin, typically found in hippocampal basket cells, suggesting that InsP(3)R1s do not play a role in internal Ca(2+) release in these interneurons. These findings should help to interpret past functional studies and inform future studies examining the characteristics and consequences of InsP(3)R-mediated internal Ca(2+) release and Ca(2+) waves in hippocampal neurons.
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PMID:Distribution of inositol-1,4,5-trisphosphate receptor isotypes and ryanodine receptor isotypes during maturation of the rat hippocampus. 1798 3


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